The generation of mice expressing human-mouse chimeric antibodies has been described by Pluschke et al., Journal of Immunological Methods 215: 27-37 (1998). The generation of mice expressing human immunoglobulin polypeptides has been described by Neuberger et al., Nature 338: 350-2 (1989); Lonberg et al., Int. Rev. Immunol. 13(1): 65-93 (1995); and Bruggemann et al., Curr. Opin. Biotechnol., 8(4): 455-8 (1997). Generation of transgenic mice using a BAC clone has been described by Yang et al., Nat. Biotechnol. 15:859-65 (1997). The generation of cows expressing human antibodies has been described by Kuroiwa et al., Nature Biotech 20(9): 889-894 (2002).
Transgenesis in animals has been described by Wall R J, Theriogenology 57(1): 189-201 (2002). The generation of transgenic rabbits has been described by Fan, J. et al., Pathol Int. 49: 583-94 (1999); and Brem et al., Mol. Reprod. Dev. 44: 56-62 (1996). The production of transgenic chicken has been described by Etches et al., Methods in Molecular Biology 62: 433-450 (1997); and Pain et al., Cells Tissues Organs 165 (3-4): 212-9 (1999); and Sherman et al., Nature Biotech 16:1050-1053 (1998).
Rabbits with impaired immunoglobulin expression have been described by Chen et al., J. Immunol. 150:2783-2793 (1993); and Lamoyi E, and Mage R G., J. Exp. Med. 162:1149-1160 (1985). A gamma-globulinemic chicken has been described by Frommel et al., J. Immunol. 105(1): 1-6 (1970); and Benedict et al., Adv. Exp. Med. Biol. 88(2): 197-205 (1977).
The cloning of animals from cells has been described by T. Wakayama et al., Nature 394:369-374 (1998); J. B. Cibelli et al., Science 280:1256-1258 (1998); J. B. Cibelli et al., Nature Biotechnology 16:642-646 (1998); A. E. Schnieke et al., Science 278: 2130-2133 (1997); and K. H. Campbell et al., Nature 380: 64-66 (1996). Nuclear transfer cloning of rabbits has been described by Stice et al., Biology of Reproduction 39: 657-664 (1988); Challah-Jacques et al., Cloning and Stem Cells 8(4):295-299 (2003).
The production of non-human transgenic animals expressing human(ized) immunoglobulin transloci and the production of antibodies from such transgenic animals have been described in detail in PCT Publication Nos. WO 92/03918, WO 02/12437, and in U.S. Pat. Nos. 5,545,807, 5,814,318; and 5,570,429. Homologous recombination for chimeric mammalian hosts is exemplified in U.S. Pat. No. 5,416,260. A method for introducing DNA into an embryo is described in U.S. Pat. No. 5,567,607. Maintenance and expansion of embryonic stem cells is described in U.S. Pat. No. 5,453,357.
The cleavage activities of viral proteins containing 2A peptide sequences have been described by Palmenberg et al., Virology 190:754-762 (1992); Ryan et al., J Gen Virol 72:2727-2732 (1991); Donnelly et al., J Gen Virol 82:1027-1041 (2001); Donnelly et al., J Gen Virol 82:1013-1025 (2001); Szymaczak et al., Nature Biotech 22(5):589-594 (2004).
So far, studies of the relative contribution of cell survival mechanisms regulated by the apoptosis inhibitor bcl-2, have been performed mainly in mice. The effect of bcl-2 expression on cell survival has been described by McDonnell et al., Cell, 57:79-88, (1989); Strasser et al., Current Topics in Microbiology and Immunology, 166:175-181, (1990); Knott et al., Hybridoma, 15 (5):365-371, (1996); Smith et al., J. Exp. Med., 191(3):475-784 (2000); Strasser et al., PNAS, 88:8661-8665, (1991) and Kumar et al., Immunology Letters, 65:153-159, (1999). The effect of the apoptosis inhibitor bcl-xL expression on cell survival has been described by Takahashi et al., J. Exp. Med., 190(3): 399-409 (1999).
Mechanisms of B-cell development such as continuous and short-term B lymphopoiesis have been reviewed in Lanning D, Osborne B A, Knight, K L., Immunoglobulin genes and generation of antibody repertoires in higher vertebrates: a key role of GALT. Molecular Biology of B-cells. Alt F. W., Honjo T, Nueberger, M. S., Eds. Elsevier London, p 443 (2004); and Flajnik M. F., Comparative analysis of immunoglobulin genes: surprises and portents. Nat. Rev. Immunol. 2:688, (2002).
Since production of antibodies in larger transgenic animals like rabbits, chickens, sheep and cows is favored from the standpoint of antibody yield, creation of larger founder animals with B-cell apoptosis inhibition expressing higher amounts of transgene-encoded products is highly desirable. However, B-cell development differs significantly in species undergoing short-term lymphopoiesis (like rabbits, chickens, sheep and cows) relative to animals characterized by continuous B lymphopoiesis (like mice). Thus, it is unclear if apoptosis inhibitors can be used with the same success in animals undergoing short-term lymphopoiesis as in the more extensively studied animals with continuous B lymphopoiesis, or, what the impact of apoptosis inhibitors on antibody production and/or antibody affinities will be.